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Title: | Acetyl derivative of quercetin 3-methyl ether-induced cell death in human leukemia cells is amplified by the inhibition of ERK | Authors: | Rubio Sánchez, Sara Quintana Aguiar, José Martín Eiroa, José L. Triana, Jorge Estévez Rosas, Francisco Jesús |
UNESCO Clasification: | 32 Ciencias médicas | Keywords: | Activated Protein-Kinase P38 Map Kinase Induced Apoptosis Cancer-Therapy Molecular-Mechanisms, et al |
Issue Date: | 2007 | Publisher: | 0143-3334 | Project: | Nuevos Compuestos Antileucémicos | Journal: | Carcinogenesis | Abstract: | Flavonoids are polyphenolic compounds that are ubiquitously in plants and display a vast array of biological activities. Here we have studied the effect of the phenylbenzo-γ-pyrone-derivative quercetin 3-methyl ether tetracetate (QD), obtained by acetylation of the natural product quercetin 3-methyl ether, on cell viability of human leukemia HL-60 and U937 cell lines. The results show that QD was cytotoxic and induced G 2 –M phase cell cycle arrest on both cell lines and it was a potent apoptotic inducer on HL-60 cells. QD-induced apoptosis is (i) mediated by caspase activation, since it was prevented by the non-specific caspase inhibitor z-VAD-fmk, (ii) associated with cytochrome c release and (iii) triggered in Bcl-2 over-expressing U937 cells. The treatment of HL-60 and U937 cells with QD also induces the activation of the mitogen-activated protein kinases (MAPKs) pathway, including c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and extracellular signal-regulated kinases (ERK) 1/2. Inhibition of c-Jun N-terminal kinase by SP600125 and of p38 mitogen-activated protein kinase by SB203580 had no influence on QD-mediated apoptosis. In contrast, inhibition of ERK1/2 with the pharmacologic inhibitors U0126 or PD98059, together with QD, resulted in an important enhancement of apoptosis. Cells are sensitized to QD-mediated apoptosis after blocking ERK1/2, which suggests that inhibition of this pathway is a valuable strategy to increase the sensitivity of human leukemia HL-60 cells toward QD. | URI: | http://hdl.handle.net/10553/43484 | ISSN: | 0143-3334 | DOI: | 10.1093/carcin/bgm131 | Source: | Carcinogenesis [ISSN 0143-3334], v. 28, p. 2105-2113 |
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